There are a large number of dermatologic diseases that are thought to be caused by microbial overgrowth or somehow result in a dermatologic infection and/or inflammatory reaction. These diseases include acne vulgaris and other pilosebaceous inflammatory disorders, which are thought to be caused in part by an overgrowth of the anaerobic bacterium Propionbacterium acnes (P acnes), which is normally present in the sebaceous follicles but proliferates in large numbers during acute acne. P. acnes generates a lipase, a protease, and other potentially damaging substances. Follicular contents are known to be chemoattractive for leukocytes, and complement activation is probably also important in the inflammatory process. Although the precise mechanisms are not entirely clear, inflammation and edema in the follicular wall result in follicular rupture, leaking follicular contents into the surrounding dermis and creating further inflammation. The visible consequence of this series of dermal events is a deep inflammatory nodule, called a "cyst." An accumulation of neutrophils in the mouth of a follicle produces a pustule. Deep inflammatory or cystic lesions may arise from preexisting closed comedones in an area of normal-appearing skin.
Genital herpes is also called "Herpes Progenitalis" and is caused by the herpes simplex virus, usually type 2. Primary genital herpes follows an incubation period of 3 to 7 days. The disease can be found by localized burning or paresthesia and followed by eruption of grouped vesicles, often at multiple sites on the genitalia. The lesions generally heal in 2 to 4 weeks, but the virus remains in the nerve heads and can remain dormant or trigger secondary lesions by migrating down the nerve fiber to the nerve ending to reproduce into more lesions. Recurrent genital herpes is common after the primary infection. Secondary lesions heal within two weeks, and secondary attacks become less frequent with time. Treatments include drying agents to symptomatically lessen the discomfort of the lesion. Acyclovir, applied topically, tends to decrease pain of the primary lesions, but it has not proven very effective for decreasing viral shedding or lesion duration. Topical acyclovir has not been shown to be particularly effective for reducing or treating recurrent disease.
Acyclovir is a purine nucleoside analog that is selectively cidal to the herpes simplex virus because only the thymidine kinase enzyme of herpes simplex virus can convert acyclovir to its monophosphate form while host cell thymidine kinase cannot. The monophosphate form is converted to an acyclovir triphosphate, which can interfere with viral DNA replication. Topical acycovir is applied as a 5% ointment every three hours, or up to eight times daily, for at least seven days. The up to eight-times-a-day dosing is a difficult procedure for patients and creates patient compliance problems for dosing in the genital areas throughout the day and throughout the night. A further problem of acyclovir has been the development of resistant strains of herpes simplex, caused by a mutation of the thymidine kinase gene. Accordingly, no backup treatments are available for acyclovir-resistant herpes simplex infections. This problem exists with most antibiotic antimicrobial treatments, but is generally not a problem for non-antibiotic treatments.
Topical fungal or yeast diseases represent a large class of diseases. These can include tinea versicolor, which is a superficial fungal infection caused by the lipophilic yeast Pityrosporum orbiculare. The infected areas do not pigment normally and produce a whitish, spotted appearance in dark-skinned or tanned persons. Treatments include the use of dandruff shampoos on the affected areas and typical antifungal agents, including the imidazole derivatives miconazoe and clotrimazoe. Fungal lesions on the skin surface are named "tinea" and the Latin name of the particular are type of location. For example, "tinea capitis" is for scalp lesions, while "tinea cruris" is for groin lesions. Tinea cruris is often manifest as symmetrical scaly patches on the inner surfaces of the thighs. The infection spreads with a central clearing area and a sharply demarcated border. Itching is common and severe. The major causitive organisms are T. rubrum, T. mentagrophytes, and Epidermophyton floccsum.
Tinea pedis is commonly called "athlete's foot." It is often caused by Trichophyton rubrum or Trichophyton mentagrophytes. It often begins as a scaly lesion between the toes and spreads to produce an acute inflammatory vesicular disease, accompanied by itching, burning and pain. Tineas corporis is also called "ringworm" and is a dermatophyte infection involving nonspecific areas of skin. The infection is an erythematous, scaly patch on the skin with sharp, acute borders and central clearing. Current treatments for topical fungal diseases include the imidazole derivatives, miconazole and clotrimazole. Griseofulvin is a systemic agent, and ketoconazole is also used systemically but is expensive and is associated with severe side effects. Side effects of griseofulvin include headaches and abdominal discomfort.
Eczema is a superficial inflammation of the skin characterized by an initial erythematous, papulovesicular process often accompanied by oozing and crusting and followed by a chronic phase of scaling, thickening and post-inflammatory pigment changes. Causes of eczema are largely uncertain but can include fungal infection. Treatments are largely symptomatic and can include topical corticosteroids for the inflammatory reaction.
Psoriasis is a papulosquamous disease characterized by chronic periodic remissions and exacerbations. Lesions usually consist of erythematous plaques with silvery scale, and possibly a pustular form. The causes of psoriasis include several theories. One theory advances that psoriasis is an inflammatory overreaction to a yeast infection, such as that caused by P. ovale. The disease is characterized histologically by accelerated cellular turnover. Psoriasis is a chronic condition and an affected individual can develop lesions at any time. Treatments vary, depending on what one believes is the cause of the disease. However, no single treatment has yet proven to be successful for a wide variety of cases.
Dandruff is a scaling condition of the scalp. It is thought to be caused by an overgrowth of P. ovale, a yeast. Treatment is usually an antimicrobial agent such a pyrithione zinc, a keratolytic agent such as salicylic acid, or by a cytostatic agent such as a coal tar.
Stasis dermatitis is a leg ulcer and is a form of eczema and often the result of venous insufficiency. It often develops in a patch just distal to where a vein was removed for a bypass procedure. Treatment is usually with a topical steroid or with an antibacterial and keratolytic agent, such as 20% benzoyl peroxide.
Acquired Immune Deficency Syndrome (AIDS) is believed to be spread by sexual contact, and more specifically, through transmission of the HIV virus. The current preventive means for tranmission by sexual contact with an individual suspected of harboring the HIV virus is a barrier, such as a condom. At present, there are no known virucidal chemical barrier preparations available that can be used alone or with a condom for prevention of the spread of HIV during sexual contact.
Anti-inflammatory agents are usually classified as steroid or non-steroidal agents. The non-steroidal anti-inflammatory agents most often function by inhibition of prostaglandin or leukotriene biosynthetic pathways. For example, non-steroidal anti-inflammatory drugs such as aspirin (acetylsalicylic acid), indomethacin, and ibuprofen are known to inhibit the fatty acid cyclooxygenase enzyme in the prostaglandin pathway from arachidonic acid. Steroid drugs have anti-inflammatory activity but also have numerous side effects, including sodium retention, hepatic deposition of glycogen, and dramatic redistribution of body fat. The steroid anti-inflammatory properties are mediated by inhibiting edema, fibrin deposition, capillary dilation, migration of leukocytes, and deposition of collagen Steroid anti-inflammatory agents have immunosuppressant side effects.
While it is difficult to give an adequate description of the inflammatory phenomenon in terms of the underlying cellular events in the injured tissue, there are certain features of the process that are generally agreed to be characteristic. These include fenestration of the microvasculature, leakage of the elements of blood into the interstitial spaces, and migration of leukocytes into the inflamed tissue. On a macroscopic level, this is usually accompanied by the clinical signs erythema, edema, tenderness (hyperalgesia), and pain. During this complex response, chemical mediators such as histamine, 5-hydroxytryptamine (5-HT), slow-reacting substance of anaphylaxis (SRS-A), various chemotactic factors, bradykinln, and prostaglandins are liberated locally. Phagocytic cells migrate into the area and cellular lysosomal membranes may be ruptured, releasing lytic enzymes. All these events may contribute to the inflammatory response. However, aspirin-like drugs have little or no effect upon the release or activity of histamine, 5-HT, SRS-A, or lysosomal enzymes; and similarly, potent antagonists of 5-HT or histamine have little or no therapeutic effect on inflammation.
The inhibition of prostaglandin biosynthesis by aspirin and other non-steroidal anti-inflammatory agents, such as ibuprofen, has been demonstrated in three different systems, cell-free homogenates of guinea pig lung, perfused dog spleen, and human platelets. There are now numerous systems in vitro and in vivo in which inhibition of prostaglandin biosynthesis by aspirin, ibuprofen, or similar compounds has been demonstrated, and it is evident that this effect is not restricted to any one species or tissue. The effect is dependent only on the drug reaching the enzyme, cycooxygenase (prostaglandin synthetase); the distribution and pharmokinetics of each agent thus have an important bearing on the drug's activity.
The migration of leukocytes into inflamed areas is an important component of inflammation. Although the classical aspirin-like drugs (salicylates, pyrazolone derivatives, ibuprofen, indomethacin, etc.) block prostaglandin biosysthesis, they do not inhibit the formation of the major chemotactic metabolite of arachidonic acid, HETE, and may even increase concentrations of this compound in tissues.
Hypoxia and ischemia are inevitable fates of any kind of tissue injury. Oxygen tension in tissue wounds, when measured by implanted polarographic oxygen electrode, was found to be only 5 to 15 mm Hg, as compared to control tissue values of 40 to 50 mm Hg. (Sheffield, "Tissue Oxygen Measurements with Respect to Soft Tissue Wound Healing with Normobaric and Hyperbaric Oxygen," Hyperbaric Oxygen Rev. 6:18-46, 1985.) Tissue ischemia is associated with an inflammatory response mediated by stimulated Hagemann factor and complement cascades. (Weiss et al., "Phagocyte-Generated Oxgen Metabolites and Cellular Injury", Lab Invest. 47:5-18, 1982.) These factors activate polymorphonucear leukocytes (PMNs) and result in a massive influx of phagocytic leukocytes into the wound. Paradoxically, the antimicromial properties of PMNs are greatly impaired in the ischemic wound region in vivo because of the lack of molecular oxygen. (Mandell, "Bactericidal Activity of Aerobic and Anaerobic Polymorphonuclear Neutrophils," Infect. Immunol. 9:337-41, 1974.) Oxygen therapy, including hyperbaric oxygen treatment, has been suggested to facilitate wound healing and is often used as adjunctive therapy in problem wounds and wound infections. However, the optimal times and mode of oxygen therapy still reman clouded. Oxygen radicals are involved in the phagocytic actions of PMNs, which, upon activation, generate superoxide and hydroxyl radicals as well as hydrogen peroxide and hypochlorous acids at the site of phagocytosis.
Any wounding, whether surgical or traumatic, causes disruption of blood vessels, tissue hemorrhage, activation of Hageman factor, and stimulation of complement pathways. These morphologic and biochemical events result in the massive influx of PMNs into the wound site and the production of superoxide radicals by PMNs as part of the phagocytic response [Reaction (i)]. The generated superoxide radicals undergo the Haber-Weiss reaction [Reaction (ii)] or iron-catalyzed Fenton type reactions [Reaction (iii)], producing cytotoxic OH radicals and H.sub.2 O.sub.2, which ultimately form hypohalite radicals via the myeloperoxidase system [Reaction (iv)]. ##STR1##
Although the presence of these oxygen-free radicals is necessary for the oxidative killing of microorganisms, excessive generation of these cytotoxic radicals may be extremely harmful to native tissues. Tissues are generally equipped with adequate antioxidative defense systems, consisting of such enzymes as superoxide dismutase, catalase, and glutathione peroxidase. However, these antioxidative enzymes are known to be reduced during ischemia and hypoxia.
Accordingly, there is a need in the pharmaceutical art for a therapeutic agent that has both strong and broad spectrum antimicrobial properties for a wide variety of bacterial, fungal, viral, and yeast infections, as well as anti-inflammatory activity, yet not be an antibiotic with the risk of developing resistant microbial strains. It is further desirable to develop a chemical agent that can be used as an antimicrobial sexual barrier and lubricating gel that has strong antiviral properties to kill active HIV virus and thereby help prevent the spread of AIDS. There is also a need in the pharmaceutical art for an anti-inflammatory therapeutic agent that does not possess the side effect problems of the aspirin-like nonsteroidal anti-inflammatory agents or the immunosuppressant properties of the corticosteroids.